Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes

Montcel, Sophie Tezenas du; Clot, Fabienne; Vidailhet, Marie; Roze, Emmanuel; Damier, Philippe; Jedynak, C. P.; Camuzat, Agnès; Lagueny, A; Vercueil, Laurent; Doummar, Diane; Guyant‐Maréchal, Lucie; Houeto, Jean‐Luc; Ponsot, G; Thobois, Stéphane; Cournelle, Marie-Anne; Dürr, Alexandra; Durif, Franck; Échenne, B.; Hannequin, Didier; Tranchant, C.; Brice, Alexis

doi:10.1136/jmg.2005.036780

Cited by 83 publications

(78 citation statements)

References 29 publications

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“…* mutation also includes 82bp of the adjacent intron. Letter-key: A - Asmus et al, 2002J -Hedrich et al, 2004aB -Asmus et al, 2005K -Hjermind et al, 2003C -Cif et al, 2004L -Klein et al, 2002aD -DeBerardinis et al, 2003M -Marechal et al, 2003E -Doheny et al, 2002bF -du Montcel et al, 2006O -O'Riordan et al, 2004G -Foncke et al, 2003P -Schule et al, 2004H -Gerrits et al, 2006Q -Valente et al, 2005I -Han et al, 2003R -Zimprich et al, 2001 Abbreviations: add. -additional; aff.…”

Section: Introductionmentioning

confidence: 99%

Myoclonus-dystonia: significance of largeSGCEdeletions

et al. 2008

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Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE.We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

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Section: Introductionmentioning

confidence: 99%

Myoclonus-dystonia: significance of largeSGCEdeletions

et al. 2008

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“…Electrophysiologic data in our family showed findings similar to those described in DYT11 M-D, but the typical distribution in DYT11 of predominantly cervical involvement with the classic retrocollic brief lightening jerks, was not seen in our patients. 12,17,26,27 Similar to that in the patients with THD described here, the myoclonus in DYT11 tends to increase with posture and action and is not stimulus sensitive. The duration of myoclonic bursts in DYT11 has a range from 25 to 256 msec (whereas cortical myoclonus is in the range of 20 to 50 msec), the C reflex is negative, and back-averaging shows no premyoclonic cortical potential, suggesting subcortical myoclonus.…”

Section: Genetic Results For Thementioning

confidence: 52%

Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

et al. 2012

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Objective: To present a new family with tyrosine hydroxylase deficiency (THD) that presented with a new phenotype of predominant, levodopa-responsive myoclonus with dystonia due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder. Methods:We performed detailed clinical examination of the family and electrophysiology to characterize the myoclonus. We performed analysis of the TH gene and in silico prediction of the possible effect of nonsynonymous substitutions on protein structure.Results: Electrophysiology suggested that the myoclonus was of subcortical origin. Genetic analysis of the TH gene revealed compound heterozygosity of a point mutation in the promoter region (c.1-71 CϾT) and a novel nonsynonymous substitution in exon 12 (c.1282GϾA, p.Gly428Arg). The latter is a novel variant, predicted to have a deleterious effect on the TH protein function and is the first pathogenic TH mutation in patients of African ancestry. Conclusion:We presented a THD family with predominant myoclonus-dystonia and a new genotype. It is important to consider THD in the differential diagnosis of myoclonus-dystonia, because early treatment with levodopa is crucial for these patients. Tyrosine hydroxylase deficiency (THD) is a rare autosomal recessive, dopa-responsive dystonia due to mutations in the TH gene.1 The phenotype of THD is thought to be a spectrum with overlap of clinical features between 2 main phenotypes 2 : one with onset of symptoms in the first year presenting as progressive hypokinetic-rigid syndrome, generalized dystonia, and good response to levodopa and the other with earlier onset presenting as a more complex encephalopathy, perinatal abnormalities, diurnal fluctuations, autonomic disturbances, and less response to levodopa.3-7 Here we present a new family with THD and a new phenotype of prominent levodopa-responsive myoclonus-dystonia (M-D) due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder.METHODS Standard protocol approvals, registrations, and patient consents.

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“…Genetic deletion of any of these four sarcoglycans in mice results in a dystrophic muscle phenotype (18). Mutations in ε-sarcoglycan cause movement disorders called myoclonus dystonia (26,33,34,44,51,52,54,59, 61) but have not been linked to cardiomyopathy or muscular dystrophy. Recessive ␦SG mutations are responsible for the cardiac and skeletal muscle phenotypes of the cardiomyopathic BIO 14.6 hamster (45,46).…”

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confidence: 99%

Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability

Campbell

Witcher

Gopal

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Campbell MD, Witcher M, Gopal A, Michele DE. Dilated cardiomyopathy mutations in ␦-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability. Am J Physiol Heart Circ Physiol 310: H1140 -H1150, 2016. First published March 11, 2016 doi:10.1152/ajpheart.00521.2015.-Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in ␦-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in ␦-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant ␦-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant ␦-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type ␦-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant ␦-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant ␦-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal ␦-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of ␦-sarcoglycan. Therefore, appropriate glycosylation of ␦-sarcoglycan may also be necessary for proper ␦-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in ␦-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of ␦-sarcoglycan-associated DCM.Listen to this article's corresponding podcast at http://ajpheart. podbean.com/e/dilated-cardiomyopathy-delta-sarcoglycan-mutationscause-cardiomyocyte-membrane-instability/. dilated cardiomyopathy; ␦-sarcoglycan; dystrophin-glycoprotein complex; mechanical strain; dye uptake THE DYSTROPHIN-GLYCOPROTEIN complex (DGC) is a large complex of transmembrane and membrane-associated proteins that resides in the lateral sarcolemma of cardiac and skeletal muscle cells. The DGC contributes to an important functional linkage between the extracellular matrix (ECM) and cytoskeletal proteins in muscle cells (20,21). The DGC attaches and interacts with the cytoskeleton through the binding of dystrophin to F-actin (62). The central transmembrane protein dystroglycan completes the link of dystrophin and the DGC to the extracellular matrix and requires the functional glycosylation of ␣-dystroglycan to serve as a high-affinity matrix receptor (38,42,62). The critical functional roles of the DGC in musc...

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Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes

Abstract: This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

Cited by 83 publications

References 29 publications

Myoclonus-dystonia: significance of largeSGCEdeletions

Myoclonus-dystonia: significance of largeSGCEdeletions

Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability

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